Haploidentical donor is preferred over matched sibling donor for pre-transplantation MRD positive ALL: a phase 3 genetically randomized study

Abstract

Background: Previous reports suggest a benefit associated with haploidentical donor transplantation (HIDT) compared to matched sibling donor transplantation (MSDT) in certain contexts, and the choice of optimal candidates warrants further investigation. Methods: We designed a prospective genetically randomized study to evaluate donor options between acute lymphoblastic leukemia (ALL) patients positive for measurable residual disease (MRD) pre-transplantation who underwent HIDT (n = 169) or MSDT (n = 39). Results: The cumulative incidence of positive MRD post-transplantation was 26% (95% CI, 19-33%) and 44% (95% CI, 28-60%) for HIDT and MSDT, respectively (P = 0.043). Compared to the HIDT cohort, the MSDT cohort had a higher 3-year cumulative incidence of relapse (CIR; 47%, 95% CI, 31-63% vs. 23%, 95% CI, 17-29%; P = 0.006) and lower 3-year probability of leukemia-free survival (LFS; 43%, 95% CI, 27-59% vs. 65%, 95% CI, 58-72%; P = 0.023) and overall survival (OS; 46%, 95% CI, 30-62% vs. 68%, 95% CI, 61-75%; P = 0.039), without a difference in non-relapse-mortality (10%, 95% CI, 1-19% vs. 11%, 95% CI, 6-16%; P = 0.845). Multivariate analysis showed that HIDT is associated with a low CIR (HR = 0.364; 95% CI, 0.202-0.655; P = 0.001) and better LFS (HR = 0.414; 95% CI, 0.246-0.695; P = 0.001) and OS (HR = 0.380; 95% CI, 0.220-0.656; P = 0.001). Conclusions: HIDT is better than MSDT in view of favorable anti-leukemia activity for patients with pre-transplantation MRD positive ALL. The current study paves the way to determine that haploidentical donors are the preferred choice regardless of available matched sibling donors in a subgroup population.

Evolving therapy of adult acute lymphoblastic leukemia: state-of-the-art treatment and future directions

“…Moreover, the recent advance of haploidentical donor HSCT, has improved transplant-related outcomes for adults with ALL, especially older patients who are more likely to lack a matched donor [151][152][153]. This may be a particularly good option for patients with MRD-positive disease, as one prospective study showed better outcomes for haploidentical donor HSCT compared with matched sibling donor HSCT in this context [154]. In addition, the acceptable non-relapse mortality and favorable survival seen in patients older than 60 years treated with reduced-intensity conditioning (with post-HSCT OS up to 45% reported in this population) have made allogeneic HSCT a more feasible approach for older/less fit patients [155][156][157].…”

Predictive Value of Dynamic Peri-Transplantation MRD Assessed By MFC Either Alone or in Combination with Other Variables for Outcomes of Patients with T-Cell Acute Lymphoblastic Leukemia

“…The study protocol was in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Peking University. All of the cases were treated according to the transplant protocol as previously described [1,17,30] .…”

“…Donor lymphocyte infusion (DLI) was performed as described previously by our group [1,17,31] . Other methods for positive MRD intervention and relapse treatment, such as interferon-γ (IFN-γ), were administered according to our previous studies [1,17,31] .…”

“…All patients were treated with a myeloablative conditioning regimen [1,17,21,30] . For patients with haploidentical donors (HIDs), the conditioning regimen was given as follows: cytarabine (4 g/m 2 per day) intravenously on days -10 to -9; busulfan (3.2 mg/kg per day) intravenously on days -8 to -6; cyclophosphamide (1.8 g/m 2 per day), intravenously on days -5 to -4; Me-CCNU (250 mg/m 2 per day), orally once on day -3; and ATG (thymoglobulin, 2.5 mg/kg per day, Sang Stat, France) intravenously on days -5 to -2.…”

The Roles of γδ T Cells in Hematopoietic Stem Cell Transplantation

“…It seems that γδ T cells can be a predict marker of relapse after HSCT. Measurable residual disease, also known as minimal residual disease (MRD), was reported as a predictor for relapse following HSCT 90 . MRD monitoring by using TRD and TRG rearrangement was demonstrated as a useful predictor for the risk of relapse in T-ALL patients with chemotherapy 91 .…”